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WO2004050104A1 - Produit medicinal a base de sauge officinale (salvia officinalis) - Google Patents

Produit medicinal a base de sauge officinale (salvia officinalis) Download PDF

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Publication number
WO2004050104A1
WO2004050104A1 PCT/GB2003/005176 GB0305176W WO2004050104A1 WO 2004050104 A1 WO2004050104 A1 WO 2004050104A1 GB 0305176 W GB0305176 W GB 0305176W WO 2004050104 A1 WO2004050104 A1 WO 2004050104A1
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WIPO (PCT)
Prior art keywords
extract
food
dried
salvia officinalis
nutraceutical
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PCT/GB2003/005176
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English (en)
Inventor
Peter John Hylands
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Oxford Natural Products PLC
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Oxford Natural Products PLC
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Priority to AU2003285543A priority Critical patent/AU2003285543A1/en
Publication of WO2004050104A1 publication Critical patent/WO2004050104A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/537—Salvia (sage)
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to the use of an extract of Salvia officinalis in improving specific aspects of cognitive function.
  • the invention also relates to a novel product which comprises this Salvia species and which is characterised by a combination of NMR and computer-based pattern recognition techniques.
  • Herbal products are increasingly used as both licensed and unlicensed medicines.
  • An increasing body of evidence is being accumulated attesting to interaction between constituents - including synergy, the modulation of activity between ingredients, which may be a potentiation of beneficial effects or an attenuation of unwanted effects - in a plant extract (Williamson, E.M. (2000) Synergy: myth or reality? in Herbal Medicine: A Concise Overview for
  • composition of the product of the invention described below is defined by a non- reductive technique involving analysis by a combination of nuclear magnetic resonance spectroscopy and principal component analysis.
  • the essential oil of the plant species Salvia lavandulaefolia has been shown to inhibit the activity of acetylcholinesterase in the hippocampus. This activity has also been confirmed ex vivo, with the demonstration of an effect similar to that of physostigmine on the contractile response of the isolated guinea pig ileum (Perry et al: J. Pharm. Pharmacol. 2001; 53;1347-56). hi addition an in -vivo experiment has demonstrated the inhibition of acetylcholinesterase in selected brain areas following oral administration of S. lavandidaefolia to aged rats (Perry et al: J. Altem. Complement. Med. 1998; 4: 419 - 28).
  • the present invention provides the use of a dried extract of Salvia officinalis in the manufacture of a medicament, food, nutraceutical or dietary supplement for improving secondary memory function or enhancing attention in a human subject.
  • the invention also provides an edible composition which comprises an edible carrier and a dried extract of Salvia officinalis, the extract being contained in an amount effective to improve secondary memory function or enhance attention in a human subject by whom the composition is consumed.
  • the composition is preferably a food product, a dietary supplement, a nutraceutical or a food additive.
  • the invention further provides a pharmaceutical composition which comprises a pharmaceutically acceptable carrier or diluent and a dried extract of Salvia officinalis, the extract being contained in an amount effective to improve secondary memory function or enhance attention in a human subject to whom the composition is administered.
  • a pharmaceutical composition which comprises a pharmaceutically acceptable carrier or diluent and a dried extract of Salvia officinalis, the extract being contained in an amount effective to improve secondary memory function or enhance attention in a human subject to whom the composition is administered.
  • One particular extract has been found to give especially good results in the cognitive tests reported in the Examples which follow.
  • That extract, which is novel is a further aspect of the present invention.
  • the present invention accordingly also provides a dried total extract of Salvia officinalis which , when submitted to analysis by a combination of NMR spectroscopy and principal component analysis (PCA), gives points on a scores plot which fall within a sphere of acceptability around the points on the scores plot of accompanying Figure 1A.
  • PCA principal component analysis
  • the dried total extract of the present invention may be inco ⁇ orated into an edible composition also comprising an edible carrier, for instance an edible composition selected from those listed above.
  • the dried total extract may alternatively be inco ⁇ orated into a pharmaceutical composition also comprising a pharmaceutically acceptable earner or diluent.
  • the dried total extract of the present invention may be used to modulate cognitive function in a human subject. Accordingly, the present invention further provides the use of a dried total extract of the invention as defined above in the manufacture of a medicament, food, functional food, nutraceutical or dietary supplement for the modulation of cognitive function in a human subject, hi one embodiment the medicament, food, functional food, nutraceutical or dietary supplement is for improving secondary memory or enhancing attention. In another embodiment it is for treating and/or delaying the onset of cognitive decline.
  • the dried extract of Salvia officinalis used in the invention in its broadest aspect is typically an extract of plant material from the aerial part of the plant, preferably the leaf, stem or flower, most preferably the leaf.
  • the extract is preferably a crude extract of the plant material used.
  • a crude extract is obtained by immersing the chosen plant material in a suitable solvent for a sufficient time for all the phytochemicals in the plant material which are soluble in that solvent to dissolve into it, and then concentrating and drying the resulting solution. No purification or separation steps are therefore involved at any stage of the process when a crude extract is desired.
  • the solvent used to produce an extract for use in the present invention is a solvent capable of dissolving as wide a range of types of compound present in plant material, both hydrophilic and lipophilic, as possible.
  • Suitable solvents include alcohols, ketones and carboxylic acid esters.
  • An alcohol may be a C ⁇ - C 6 alcohol, for instance methanol, ethanol, isopropyl alcohol, n-butyl alcohol, t-butyl alcohol or amyl alcohol.
  • a ketone may be acetone.
  • a carboxylic acid ester is typically a C ⁇ -C 6 alkyl ester of a carboxylic acid, for instance ethyl acetate.
  • An aqueous solvent may also be used, for instance an aqueous alcohol such as aqueous ethanol, preferably 70% ethanol.
  • the extract contains two or more of the constituent phytochemicals of the Salvia officinalis raw plant material. Preferably it is a total extract, most preferably a total extract of dried leaf material.
  • total extract is meant an extract comprising all, or substantially all, of the constituent phytochemicals of the plant material which are soluble in the solvent used to produce the extract.
  • a total extract consequently reflects the totality of the active components present in the plant material.
  • a prefened extract for use in the present invention is a dried ethanolic extract of dried leaf material of Salvia officinalis.
  • a typical process for producing an extract of Salvia officinalis for use in the present invention comprises soaldng dry cleaned leaf material in the chosen solvent at room temperature for a period of time ranging from 6 hours to 72 hours, separating the resulting solution from the residual solid plant material, concentrating the solution to form a concentrate and then drying the concentrate.
  • the dried concentrate is typically milled to yield dried extract in powder form.
  • the soaking step preferably takes from 12 hours to 60 hours, more preferably from 24 hours to 60 hours, most typically about 48 hours.
  • the soaking step may be repeated one or more times using a fresh batch of solvent each time.
  • the resulting solutions are then combined and concentrated.
  • the extraction step may be carried out with warming and/or under pressure.
  • the temperature to which the solution is wanned depends upon the solvent used; for 70% aqueous ethanol a suitable temperature at atmospheric pressure is from room temperature to about 80°C, typically from about 40°C to about 80°C.
  • the use of warming and/or pressure significantly reduces the residence time of plant material in solvent required to achieve the desired level of extraction.
  • the chosen Salvia officinalis plant material may be extracted using any other suitable technique, for instance using supercritical CO 2 extraction.
  • the concentration step is carried out by any suitable means, for instance in a climbing film evaporator or in a finishing still under vacuum. More than one concentration step may be performed if required.
  • the resulting concentrate is dried by any suitable means, for instance in a vacuum oven or by freeze drying or lypophilisation. It may tlien be milled to a powder having any desired mesh size, for instance 44 mesh.
  • a particular dried ethanolic total extract of Salvia officinalis is novel. This is an extract produced as described above from dried clean leaf of plant material that was grown in England at a latitude between 51° and 53° north and a longitude between 1° and 3° west, in soil that was either sand/sandy loam or chalk/chalky loam.
  • the plant material was grown to defined production protocols meeting Good Agricultural Practice (GAP) standards and was harvested between November and March.
  • GAP Good Agricultural Practice
  • the leaf was dried at temperatures less than 60° C, either by artificial heating or by the application of dehumidified blown air.
  • the above extract gives results which are differentiated from those obtained from plant material of (a) different Salvia species; (b) different varieties of Salvia officinalis, grown either elsewhere or in the same location; and (c) the same variety of Salvia officinalis grown under the same conditions at the same geographic locations but harvested outside the defined harvest period.
  • the extract is referred to herein as ONP-22 and is novel.
  • the combination of 1H NMR spectroscopy and pattern recognition is described in full in WO 00/47792.
  • the technique takes account of the totality of components in the plant material that respond to the NMR spectroscopic technique being used and comprises: (a) submitting the plant extract to NMR spectroscopy and recording one or more NMR spectra; and
  • a scores plot is a graphical representation in which samples are projected into the space spanned by two or more principal component axes.
  • Principal component analysis (PCA) and validated PCA are particular methods used to analyse data included in a multivariate analysis, hi PCA the positions of the samples can be plotted in a scores plot in two or more dimensions where similar samples will tend to form clusters while dissimilar samples will tend to be spread over large distances.
  • a multidimensional volume of acceptability such as a sphere or ellipse, is defined around the point or points on the scores plot generated in step (b) above when the NMR/pattem recognition analysis is applied to the ONP-22 product. That volume then constitutes the, or part of the, standard specification for the product.
  • subsequent samples can be tested for compliance with it. Accordingly, candidate dried ethanolic extracts of Salvia officinalis can be accepted or rejected as complying with the ONP-22 standard depending whether, when submitted to the NMR/pattem recognition analysis defined above, they give points on a scores plot that fall within or outside the defined multidimensional volume of acceptability.
  • the context in which the points are generated on the scores plot must be identical when analysing candidate extracts of Salvia officinalis for compliance with the ONP-22 standard as when the original ONP-22 product was characterised.
  • the components of the methodology used to establish the positioning of the point or points on the scores plot for the known sample used to define the standard must be present when the NMR spectroscopic data from the candidate samples are processed.
  • the data derived from the NMR spectrum of the ONP-22 candidate sample are subjected to appropriate manipulation by multivariate statistical methods, for example principal component analysis or canonical variation, together with those of the standard.
  • the multidimensional volume is defined by limits in the score plot which have been established on the basis of the position in the score plot of points derived from one or more extracts of a sample of ONP-22. It is prefened that the multivariate analysis be performed using an unsupervised methodology.
  • the NMR spectroscopic technique may involve carrying out 1H NMR spectroscopy at high fields in combination with multivariate analysis.
  • the NMR spectra are typically measured at 400 to 800 MHz.
  • the data derived from them are then analysed by multivariate analysis software, for instance the commercially available "Pirouette" package.
  • 1- dimensional NMR spectroscopy using other NMR-active nuclei such as 13C or 2H may be used in the present invention. It is also possible to use a range of 2- dimensional pulse sequence spectroscopic investigations with 1H or other NMR- active nuclei such as those mentioned above. The same principles apply in each case, though, and the results are analysed by appropriate multivariate analysis.
  • the NMR spectra may be normalised or non-normalised before the computer-based pattern recognition is carried out. Normalisation is typically carried out when the main objective of the procedure is to highlight qualitative differences between spectra obtained from different samples. However, in some cases peak intensity may be required as a discriminating factor when absolute quantitative values, for instance potency, are required. In such situations the spectra are non- nomialised.
  • NMR spectroscopy/pattern recognition is that it is not limited by a selective delivery or detection system. Spectra can be recorded without prior purification of the test extract, thus allowing all components of the sample which possess a hydrogen atom to contribute to the overall NMR spectrum of the complex mixtures of components contained in plant materials.
  • the approach used for defining ONP-22 includes setting a specification for Dried Raw (plant) Material (DRM) and Botanical Drug Substance (BDS) exfracts.
  • DRMs are usually samples of plant material taken from the field or are representative samples of commercially harvested plant materials.
  • BDSs are dried solvent exfracts of commercially available or large-scale plant harvested materials.
  • the NMR/pattem recognition method described above can be used to distinguish between similar plant species, the same plant species obtained from different sources or fields, and samples that may have been accidentally or deliberately contaminated by similar plant materials or different plant materials that may have been co-harvested with the desired material.
  • the overall process for providing a specification for a dried raw material (DRM), or for testing whether a sample of DRM reaches the necessary specification typically comprises: i) grinding and chopping a representative plant sample of dried raw plant material from a source of known provenance; ii) extracting the phytochemicals in the plant material using a standardized method to reduce variability; iii) drying the extracted material to ensure that residual solvents used in the extraction process are removed; iv) preparing a test solution of the extract of the plant material; v) submitting the test solution to NMR spectroscopy and recording one or more
  • NMR spectra a sample which complies or not with a previously set standard specification known as the Target Species (TS).
  • TS Target Species
  • the process for providing a specification for a botanical drag substance (BDS) or for testing if a sample of BDS reaches the necessary specification is essentially the same as that for a dried raw material.
  • BDS botanical drag substance
  • the BDS is a dried ethanolic extract of a commercially haivested crop of Salvia officinalis of known provenance.
  • a representative sample of the BDS is taken, usually of about 5g. If desired the sample can be re-extracted using a standardized method to reduce variability and then further dried to remove traces of extraction solvents.
  • the sample can be used directly without any further treatment. It can if necessary be further dried if the BDS contains appreciable amounts of solvents used in the commercial extraction process. Analogous approaches may be taken to achieve a specification for a dried raw material (DRM).
  • DRM dried raw material
  • a test solution of the extract of the plant material is then prepared, the test solution is submitted to NMR spectroscopy and one or more NMR spectra are recorded.
  • the data obtained from the NMR spectra are submitted to a multivariate analysis to generate one or more points on a scores plot as described above and the sample is selected as a sample which complies or not with a previously established standard specification for the BDS.
  • Secondary memory relates to the storage of an unlimited amount of information long-term. It is the memory for an event that is not currently in a subject's attention. It may therefore involve the retrieval of infomiation that has been stored outside of conscious awareness.
  • the present invention provides the use of a dried extract of Salvia officinalis in the manufacture of a medicament, food, functional food, nutraceutical or dietary supplement for use in improving secondary memory function or enhancing attention in a human subject.
  • the subject may be a healthy elderly subject.
  • the temi "elderly” in this context means aged from 60 upwards, typically from 65 upwards, more typically from 70 upwards, preferably from 75 upwards.
  • the term "healthy” in this context means that the cognitive function of the subject is not impaired or compromised, for instance by illness, age-related decline or genetic factors.
  • the subject may alternatively be a subject of any age who is suffering from, is at risk of suffering from, or has a predisposition towards, a neurodegenerative disorder.
  • the neurodegenerative disorder may be, for instance, Parkinson's disease or Alzheimer's disease.
  • the subject may be a pre- Alzheimer's patient, a patient in whom the first symptoms of Alzheimer's disease have been detected, a patient in whom Alzheimer's disease has just been diagnosed or a patient with well- established Alzheimer's disease.
  • the medicament, food, functional food, nutraceutical or dietary supplement containing the extract of Salvia officinalis is for improving the quality of life of an Alzheimer's patient.
  • the medicament, food, functional food, nutraceutical or dietary supplement containing the extract of Salvia officinalis is for treating, or delaying the onset of, cognitive decline.
  • the decline may be age- related or may be the result of an illness or disorder, for instance a neurodegenerative disorder as described above.
  • the medicament, food, functional food, nutraceutical or dietary supplement containing the extract of Salvia officinalis is for modulating cognitive function in a healthy young subject.
  • the tenri "young" in this context means less than 50 years of age, typically less than 45 years, more preferably less than 40 years.
  • the young subject may be a teenager or a young adult from 20 to 30 years of age.
  • the medicament, food, functional food, nutraceutical or dietary supplement containing the extract of Salvia officinalis may be used to enliance perfomiance by the subject in tasks requiring memory and attention. Such tasks include, for instance, preparing for and taking examinations.
  • the dried extract is administered in an amount of from 50mg to 1500mg per dose, typically from lOOmg to 1200mg, more preferably from 250mg to lOOOmg, still more preferably from 300mg to 700mg.
  • Doses of 333mg and 667mg are prefened, particularly 333mg.
  • the dose may be taken one or more times a day, every other day, once a week, once every ten days, or as required. It may be taken as directed by a medical practitioner, including a practitioner of herbal medicine or a nutritional therapist. It may be taken as part of a diet regimen or course of nutritional therapy. It may alternatively be taken inegularly or intermittently, for instance only on specific occasions as and when required.
  • the dose may be delivered as a dietary supplement, for instance in a standard unit dosage foimat such as a capsule or tablet, or it may be inco ⁇ orated into a food, functional food, nutraceutical or medicament, for instance as described below.
  • a dried extract of Salvia officinalis is formulated into a medicament, food product, nutraceutical or dietary supplement for administration to a human subject for the modulation of cognitive function.
  • a food is an edible material composed primarily of one or more of the niacronutrients protein, carbohydrate and fat, which is used in the body of an organism to sustain growth, repair damage, aid vital processes or furnish energy.
  • a food may also contain one or more micronutrients such as vitamins or minerals, or additional dietary ingredients such as flavourants and colourants.
  • the term food as used herein also covers a beverage. Examples of foods into which the dried extract may be inco ⁇ orated include snack bars, cereals, baked goods, dips and spreads, confectionery, probiotic formulations including yoghurts, frozen confections and salad dressings. Examples of beverages include soft beverages, dry drink mixes, nutritional beverages and herbal teas for infusion or herbal blends for decoction in water.
  • a nutraceutical is a food ingredient, food supplement or food product which is considered to provide a medical or health benefit, including the prevention and treatment of disease.
  • a nutraceutical is specifically adapted to confer a particular health benefit on the consumer.
  • a nutraceutical typically comprises a micronutrient such as a vitamin, mineral, herb or phytochemical at a higher level than would be found in a conesponding regular food product. That level is typically selected to optimise the intended health benefit of the nutraceutical when taken either as a single serving or as part of a diet regimen or course of nutritional therapy.
  • a functional food is a food that is marketed as providing a health benefit beyond that of supplying pure nutrition to the consumer.
  • a functional food typically inco ⁇ orates an ingredient such as a micronutrient as mentioned above, which confers a specific medical or physiological benefit other than a nutritional effect.
  • a functional food typically canies a health claim on the packaging.
  • a nutraceutical or functional food product contains an extract of Salvia officinalis, typically ONP-22, in an amount effective to modulate cognitive function, preferably to improve secondary memory or enliance attention.
  • a dietary supplement is a product that is intended to supplement the normal diet of a human subject and which contains a dietary ingredient such as a vitamin, mineral, herb or other botanical product, or amino acid.
  • a dietary supplement is typically presented in unit dosage format and is designed for consumption with, before or after food but not in place of food.
  • a dietary supplement is thus often presented as a tablet or capsule, or as dried powder or granules for sprinkling over food or adding to water or a beverage.
  • a dried extract of Salvia officinalis may be fonnulated into a medicament or dietary supplement by mixing with a dietetically or pharmaceutically acceptable earner or excipient.
  • a carrier or excipient may be a solvent, dispersion medium, coating, isotonic or absoiption delaying agent, sweetener or the like. These include any and all solvents, dispersion media, coatings, isotonic and absoiption delaying agents, sweeteners and the like.
  • Suitable carriers may be prepared from a wide range of materials including, but not limited to, diluents, binders and adhesives, lubricants, disintegrants, colouring agents, bulking agents, flavouring agents, sweetening agents and miscellaneous materials such as buffers and adsorbents that may be needed in order to prepare a particular dosage form.
  • diluents binders and adhesives
  • lubricants disintegrants
  • colouring agents e.g., lubricants, disintegrants, colouring agents, bulking agents, flavouring agents, sweetening agents and miscellaneous materials
  • buffers and adsorbents such as buffers and adsorbents
  • the solid oral fom s may contain, together with the active compound, diluents such as lactose, dextrose, saccharose, cellulose, com starch or potato starch; lubricants such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose, or polyvinyl pyrrolidone; disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs, sweeteners; wetting agents such as lecithin, polysorbates, lauryl sulphates.
  • diluents such as lactose, dextrose, saccharose, cellulose, com starch or potato starch
  • lubricants such as silica, talc, stearic acid, magnesium or calcium stearate and/or
  • Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
  • the syrups may contain as carrier, for example, saccharose or saccharose with glycerol and/or mamiitol and/or sorbitol.
  • a syrup for diabetic patients can contain as earners only products, for example sorbitol, which do not metabolise to glucose or which only metabolise a very small amount to glucose.
  • the suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.
  • the extract of Salvia officinalis is also suitably fonnulated into granules or a powder. In this fomi it can be readily dispersed in water or other liquid such as tea or a soft chink for human patients to drink. It may also be encapsulated, tabletted or formulated with a physiologically acceptable vehicle into unit dosage forms.
  • a unit dosage can comprise a therapeutically effective amount of the extract for a single daily administration, or it can be formulated into smaller quantities to provide for multiple doses in a day.
  • the composition may thus, for instance, be formulated into tablets, capsules, syrups, elixirs, enteral formulations or any other orally administrable fonn.
  • physiologically acceptable caniers include water, oil, emulsions, alcohol or any other suitable material.
  • Figure 1A is a 3-D Soft Independent Modelling of Class Analogies (SLMCA) scores plot of factors 1, 2 and 3 for a number of samples of ONP-22 material.
  • SMCA Soft Independent Modelling of Class Analogies
  • Figure IB is a 2-D principal components analysis (PCA) scores plot for a number of samples of ONP-22 material (first three factors).
  • PCA principal components analysis
  • Figure 2 is a PCA scores plot of ONP-22 against two different species of Salvia, in which the symbol ( ⁇ ) denotes ONP-22, (0) denotes Salvia lavandulaefolia and (0) denotes Salvia fruticosa which are labelled on the Figure.
  • Figure 3 is an outliers diagnostic chart of the data contained in Figure 2, wherein the X axis shows the Mahalanobis distance and the Y axis shows the residual distance.
  • Figure 4 is a PCA score plot of ONP-22 against samples of Salvia officinalis produced in the following non-target areas: ( ⁇ ) denotes target area; (0) denotes UK, (0) denotes Weg and (0) denotes Italy which are labelled on the Figure.
  • Figure 5 is an outliers diagnostic chart of the data contained in Figure 4, wherein wherein the X axis shows the Mahalanobis distance and the Y axis shows the residual distance.
  • Figure 6 is a PCA score plot of ONP-22 against samples of Salvia officinalis harvested at a different time in the season, wherein ( ⁇ ) denotes ONP-22 and (0) denotes sample harvested out of season.
  • Figure 7 is a diagnostic outliers chart of the data contained in Figure 6, wherein the X axis shows the Mahalanobis distance and the Y axis shows the residual distance.
  • Figure 8 shows the effect of ONP-22 in a CDR computerised assessment battery in which (•) denotes placebo, (A) denotes a dose of 167 mg, ( ⁇ ) denotes a dose of 333 mg, (T) denotes a dose of 666 mg, and ( ⁇ ) denotes a dose of 1332 mg.
  • the x axis represents time and the y axis represents change in score from baseline.
  • Figure 9 shows the effect of ONP-22 as percentage change compared with placebo on secondary memory ("long term memory”) as assessed by the CDR computerised assessment battery, wherein each A represents a dose of 167mg; each B represents a dose of 333mg; each C represents a dose of 666mg; and each D represents a dose of 1332mg.
  • Dry cleaned leaf material of Salvia officinalis (200kg) was soaked in 70% aqueous ethanol for 48 hours and the resulting liquor was drawn off. This process was repeated using a fresh batch of solvent. The liquor from the two operations was then concentrated in a climbing film evaporator and further concentrated in a finishing still under vacuum. The final concentrate was then dried in a vacuum oven. The resulting dried cake was then milled to pass through a 44 mesh sieve.
  • TRM target raw material
  • NTS non-target species
  • Representative samples of dried raw material of the aerial parts of the three plant's species were ground and mixed in a blender, lg portions of each were weighed in triplicate on a top-pan balance and the samples placed in a Dionex ASE- 200 Accelerated Solvent Extractor cell together with enough sable sand to completely fill the cells.
  • the plant materials were extracted under identical conditions at 80°C using 70%) ethanol and 30% pure water for 15 minutes at 1250-psi pressure.
  • the resulting solution (33ml) was then placed in a vacuum centrifuge parallel evaporator (Christ Beta RVC) to remove the solvents. Care was taken to ensure that the samples were not exposed to excessive heat during this process.
  • lml of pure water (Millipore Elix) was added to each dried extract and the mixtures were placed in an ultrasonic bath for about 30 seconds.
  • the aqueous mixtures were then placed in a freezer at -85° for at least 30 minutes. When the solutions were completely frozen the samples were then placed in a freeze-drier overnight or until visibly dry.
  • NMR spectra were integrated using a transfonrier tool to reduce the spectra into "histograms" containing buckets of 0.04ppm and the resultant data were normalized using the sum of the entire spectrum.
  • the resulting file was opened in Excel and the data were subjected to multivariate analysis using the Pirouette software package (from Infometrix Inc, Woodinville, WA).
  • FIG. 2 is a 3-D plot of TRM versus NTS.
  • the Salvia fruticosa points are denoted (0) and Salvia lavandidaefolia points are denoted (0).
  • the multivariate analysis technique used to produce Figure 2 is Soft Independent Modelling of Class Analogies (SLMCA). There is clearly no overlap between the ellipsoids showing confidence limits for the TRM and the NTS materials. The differences between the groups were examined further as described below.
  • Example 3 The setting of the specification of novel dried extract of target raw material against target species from non-target producers.
  • Example 2 The experimental procedure used in Example 2 was repeated, but using samples of Salvia officinalis obtained from non-target production sites in place of the two non-target Salvia species.
  • Figure 4 is a 3-D (SLMCA) plot of target raw material (TRM) against tliree non-target production (NTP) samples.
  • TRM target raw material
  • NTP tliree non-target production
  • Example 4 The setting of the specification of ONP-22 target raw material when the raw material sample had been harvested at different times through the season or in different years
  • Example 2 The experimental procedure described in Example 2 was repeated, but using samples of dried raw material of Salvia officinalis harvested at a different time in the season and in different years from the target raw material in place of the two non-target Salvia species.
  • the reduced data were included with those from earlier experiments and are shown in accompanying Figures 6 and 7.
  • TRM includes all data from commercial harvests to date. Limits- to-specification material (denoted (0) ) was harvested outside of the prescribed season, and differs phytochemically from the desired TRM, as is demonstrated above (the confidence limits for the two groups do not overlap).
  • a validated Principal Components model was created to describe the TRM data and run against the NTP data; the resultant data is used to generate an outliers diagnostic chart divided into four quadrants. Samples falling outside both the x- and y- critical tliresholds are significantly different from the modelled population. Our example shows that the out-of season samples are distinctly materially different from those of the TRM.
  • Example 5 The setting of the specification of ONP-22 Botanical Drag Substance from the target raw material
  • This experiment allowed a comparison of Botanical Drag Substance (BDS) prepared from target raw material to be compared with other samples prepared in a similar manner from either other target raw material or from non-target raw material
  • the ONP-22 BDS was prepared from ethanol/water as described in Example 1. This extract can be used directly or can be re-extracted as described in Example 2.
  • NMR samples were prepared by weighing lOmg samples of the BDS or an extract of the BDS in duplicate or triplicate and obtaining NMR spectra as described in Example 2 above.
  • Example 6 The effect of acute administration of ONP-22 on cognitive perfomiance in healthy elderly volunteers
  • CDR Cognitive Drag Research
  • Word Presentation Fifteen words, matched for frequency and concreteness, were presented in sequence on the monitor for the participant to remember. Stimulus duration was 1 second, as was the inter-stimulus interval.
  • Immediate Word Recall The participant was allowed 60 seconds to write down as many of the words as possible. The task was scored as number of words produced, minus errors and infrusions and the resulting score was converted into a percentage.
  • Picture Presentation A series of 20 photographic images of everyday objects and scenes were presented on the monitor at the rate of 1 every 3 seconds, with a stimulus duration of 1 second, for the participant to remember.
  • Digit Vigilance Task A target digit was randomly selected and constantly displayed to the right of the monitor screen. A series of digits were presented in the centre of the screen at the rate of 80 per minute and the participant was required to press the 'YES' button as quickly as possible every time the digit in the series matched the target digit. The task lasted one minute and there were 15 stimulus-target matches. Task measures were accuracy (%>), reaction time (msecs) and number of false alarms.
  • Choice Reaction Time Either the word 'NO' or the word 'YES' was presented on the monitor and the participant was required to press the conesponding button as quickly as possible. There were 50 trials, of which the stimulus word was chosen randomly with equal probability, with a randomly varying inter-stimulus interval of between 1 and 3.5 seconds. Reaction times (msec) and accuracy (%>) were recorded.
  • Spatial Worldng Memory A pictorial representation of a house was presented on the screen with four of its nine windows lit. The participant was instracted to memorise the position of the illuminated windows, h 36 subsequent presentations of the house, one of the windows was illuminated and the participant decided whether or not this matched one of the lighted windows in the original presentation. The participant made their response by pressing the 'YES' or 'NO' response button as quickly as possible. Mean reaction times were measured in msec, and accuracy of responses to both original and novel (distractor) stimuli were recorded as percentages which were used to derive a '%> greater than chance perfomiance' score.
  • Numeric Working Memoiy Five digits were presented sequentially for the participant . to hold in memory. This was followed by a series of 30 probe digits for each of which the participant decided whether or not it had been in the original series and pressed the 'YES' or 'NO' response button as appropriate as quickly as possible. This was repeated two further times with different stimuli and probe digits. Mean reaction times were measured in msec, and accuracy of responses to both original and novel (distractor) stimuli were recorded as percentages which were used to derive a '% greater than chance performance' score. . Delayed Word Recall: The participant was again given 60 seconds to write down as many of the words as possible. The task was scored as number conect, errors and intrusions and the resulting score was converted into a percentage.
  • Delayed Word Recogmtion The original words plus 15 distractor words were presented one at a time in a randomised order. For each word the participant indicated whether or not he recognised it as being included in the original list of words by pressing the 'YES' or 'NO' button as appropriate and as quickly as possible. Mean reaction times were measured in msec, and accuracy of responses to both original and novel (distractor) stimuli were recorded as percentages which were used to derive a '% greater than chance perfomiance' score.. Delayed Picture Recognition: The original pictures plus 20 distractor pictures were ' presented one at a time in a randomised order.
  • 'Quality of Memory ' measure derived by combining the 'Secondary Memory' and 'Working Memory' factor scores (see below).
  • 'Secondaiy Memory 'factor derived by combining the percentage accuracy scores (adjusted for proportions of novel and original stimuli where appropriate) from all of the secondary memory tests - word recognition, picture recognition, immediate word recall and delayed word recall (with adjustments to the total % conect for enors and intrusions on the latter two tasks). One hundred percent accuracy across the four tasks would generate a maximum score of 400 on this index.
  • Speed of memory factor derived by combining the reaction times of the four computerised memory tasks - Numeric working memory, Spatial Memory, Delayed word recognition and delayed picture recognition (units are summed milliseconds for the 4 tasks). Attention
  • Speed of attention factor derived by combining the reaction times of the tliree attentional tasks - simple reaction time, choice reaction time and digit vigilance (units are summed milliseconds for the 3 tasks).
  • capsules On each study day participants received four capsules that were of identical appearance on each occasion.
  • the individual capsules contained either an inert placebo, 167mg or 333mg of dried extract of Salvia officinalis leaf.
  • the combination of capsules conesponded to a dose of either 0 (placebo), 167mg, 333mg, 666mg or 1332mg of dried extract of Salvia officinalis..
  • Each study day comprised five identical testing sessions. The first was a pre-dose testing session which established baseline perfomiance for that day, and was immediately followed by the day's treatment on visits 2 to 6. Further testing sessions began at 1 hour, 2.5 hours, 4 hours and 6 hours following consumption of the day's treatment. Each testing session comprised completion of the Bond-Lader Visual Analogue Scales, the CDR test battery, and finally the Serial 3s and Serial 7s computerised subtraction tasks.
  • Cognitive factor outcome measures Mean pre-dose baseline raw scores, and change from baseline scores for each condition at each post-dose time point on the individual task outcome measures are presented in Figure 8. Results on individual task outcomes are described in relationship to the overall factor to which they contribute below (memory task results are presented with the relevant factor i.e. 'Secondary' or 'Working' memory).

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Abstract

La présente invention concerne l'utilisation d'un extrait sec de sauge officinale (Salvia officinalis) dans la fabrication d'un médicament, d'un aliment, d'un aliment fonctionnel, d'un complément alimentaire ou nutraceutique, afin d'améliorer la fonction de la mémoire secondaire ou de renforcer l'attention chez un sujet humain. Cette invention concerne également un extrait brut sec de Salvia officinalis permettant d'obtenir des résultats uniques lorsqu'il est soumis à une analyse combinée alliant la spectroscopie RMN et la reconnaissance des formes. Ce nouvel extrait peut être utilisé pour moduler la fonction cognitive.
PCT/GB2003/005176 2002-11-29 2003-11-28 Produit medicinal a base de sauge officinale (salvia officinalis) Ceased WO2004050104A1 (fr)

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AU2003285543A AU2003285543A1 (en) 2002-11-29 2003-11-28 Herbal product of salvia officinalis

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GB0227972.7 2002-11-29
GBGB0227972.7A GB0227972D0 (en) 2002-11-29 2002-11-29 Herbal product

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8017168B2 (en) 2006-11-02 2011-09-13 The Coca-Cola Company High-potency sweetener composition with rubisco protein, rubiscolin, rubiscolin derivatives, ace inhibitory peptides, and combinations thereof, and compositions sweetened therewith
US9101160B2 (en) 2005-11-23 2015-08-11 The Coca-Cola Company Condiments with high-potency sweetener

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4942033A (en) * 1983-12-27 1990-07-17 L'oreal Vegetable extract-based cosmetic or pharmaceutical composition which acts on capillary brittleness
WO1993006190A1 (fr) * 1991-09-20 1993-04-01 Norac Technologies Inc. Compositions oleoresineuses antioxydantes et procede de preparation
US20010056121A1 (en) * 1999-12-02 2001-12-27 Kunio Kosaka Method of promoting synthesis of nerve growth factor
DE10116175A1 (de) * 2001-03-28 2002-11-14 Bombastus Werke Ag Verwendung von löslichem Stoffinventar aus Wurzeln von Salvia officinalis zur Behandlung von ulcerösen Zuständen im Magen-Darmtrakt

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4942033A (en) * 1983-12-27 1990-07-17 L'oreal Vegetable extract-based cosmetic or pharmaceutical composition which acts on capillary brittleness
WO1993006190A1 (fr) * 1991-09-20 1993-04-01 Norac Technologies Inc. Compositions oleoresineuses antioxydantes et procede de preparation
US20010056121A1 (en) * 1999-12-02 2001-12-27 Kunio Kosaka Method of promoting synthesis of nerve growth factor
DE10116175A1 (de) * 2001-03-28 2002-11-14 Bombastus Werke Ag Verwendung von löslichem Stoffinventar aus Wurzeln von Salvia officinalis zur Behandlung von ulcerösen Zuständen im Magen-Darmtrakt

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PERRY E K ET AL: "MEDICINAL PLANTS AND ALZHEIMER'S DISEASE: FROM ETHNOBOTANY TO PHYTOTHERAPY", JOURNAL OF PHARMACY AND PHARMACOLOGY, LONDON, GB, vol. 51, no. 5, May 1999 (1999-05-01), pages 527 - 534, XP009024333, ISSN: 0022-3573 *
PERRY NICOLETTE ET AL: "European herbs with cholinergic activities: Potential in dementia therapy", INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, vol. 11, no. 12, 1996, pages 1063 - 1069, XP009027601, ISSN: 0885-6230 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9101160B2 (en) 2005-11-23 2015-08-11 The Coca-Cola Company Condiments with high-potency sweetener
US8017168B2 (en) 2006-11-02 2011-09-13 The Coca-Cola Company High-potency sweetener composition with rubisco protein, rubiscolin, rubiscolin derivatives, ace inhibitory peptides, and combinations thereof, and compositions sweetened therewith

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AU2003285543A1 (en) 2004-06-23
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